CA1190922A

CA1190922A - Pyridoxine derivatives, a process for their preparation and related pharmaceutical compositions

Info

Publication number: CA1190922A
Application number: CA000388324A
Authority: CA
Inventors: Alberto Reiner
Original assignee: D&D SRL
Current assignee: D&D SRL
Priority date: 1980-10-21
Filing date: 1981-10-20
Publication date: 1985-07-23
Also published as: JPS5795962A; EP0050385A1; AR230747A1; ES8207142A1; PT73844A; AU551422B2; JPH0343268B2; AU7662281A; NO159855B; IT1133963B; IT8025473A0; YU251981A; ES506375A0; DE3173724D1; US4412996A; YU42439B; NO813537L; FR2492375A1; NO159855C; BE890798A

Abstract

ABSTRACT OF THE DISCLOSURE

The esters of pyridoxine and of isopropylidene pyridoxine with 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-indol-3-acetic acid and 5-(2,4-difluorophenyl)-salicyclic acid are essentially endowed with the same activities of the corresponding acids and are less toxic and gastrolesive, whereby the therapeutical index is remarkably improved.
For the preparation of these compounds the chloride of the acid is reacted with isopropylidene pyridoxine, followed by a hydrolysis to obtain the corresponding pyridoxine deri-vative.

Description

,- - 2 -The present invention relates to therepeutically active derivatives of pyridoxi-ne and isopropylidene pyridoxine, having general formula:
ûR

R1 OH;~C ~ OR (I) It~ N/L~ CH3 wherein each R represents hydrogen or, the two Rs in com-bination, an isopropylidenq~group,, and Rl represents the residue of an acid of the group cornprising l-(p-cholorobenzoyl)-2-rnethyl-5-methoxy-indol-3-acetic acid and 5-(2,4-difluoro-phenyl)-salicyiic acid, and the related salts with inorganic and organic, non toxic and pharmaceutically acceptable acids.
The l-(p-chlorobenzoyl)-2-methyl-5-methoxy-indol-3-acetic acid, also known with the generical namE of "Indomethacin", is endowed with remarkable anti-inflamrnatory, anti-phlogistic and analgesic properties and activities, which however are accompanied by not negligible phenomena of gastric intolerance and ulcerogenicity as well as of relevant toxicity, whereby the use thereof is seriously limited, especially in the case of extended treatments, and particularcautions and controls are anyhow necessary.
~ like problem, although in a dilferent magnitude, exists for the 5-(2,4-di fluorophenyl)-salicylic acid, also known under the non chemical name of "Di Flunisal".
An indication of the problerns and difficulties related to the aforesaid active principles can be obtained from the fact that, despite their high activity (Indomethacin is often taken as the reference comparison compound for the evaluation of the anti-inflammatory activity of other compounds), these drugs are used in the more serious cases, when other less toxic active substances fails as regards the therapeutical airn.
It has been now found that the esters according to the present invention maintain the therapeutical properties of the free acids, especially as regards the analgesic activity, but show relevantly reduced toxicity and gastrolesivity,whereby the therapeutical index is remarkably improved in comparison with the free acid. e~

Another feature of the present invention Pesides in the process for thepreparation of esters of pyridoxine and isopropylidene pyridoxine, particularly of the compounds of the invention.
Such a process, in fact, comprises the reaction, in an anhydrous and inert solvent~ of isopropylidene pyridoxine with the chloride of the acid, in the presence of an acid acceptor, particularly a tertiary amine, as the catalyst, and the hydrolysis step when the desired derivative is the pyridoxine ester.
In turn of the hydrolysis should be carried out, according to the methods konwn in the art, (as in the case of like compounds) in acidic environment and in hot condition.
However, in the case of the pyridoxine ester of l-(p-chlorobenzoyl)-2-methyl-5^methoxy-indol-3-acetic acid, the carrying out of the hydrolysis under the standard conditions for the conversion from isopropylidene pyridoxine into pyridoxine ester would not only lead to the removal of the isopropylidene group, which is a desired occurrencc, but also to the splitting of the p-chlorobenzoic group, which is not desired, with the easily understandable consequences.
Another problem related to the known process of acidic hydrolysis and relating not only to the pyridoxine ester of Indomethacin, but to all esters of pyridoxine with organic acids, particularly with 5-(2,4-difluorophenyl)-salicylic acid, 2-hydroxybenzoyl acid1 2- (2,3-dimethylphenyl)-amino -benzoic acid, ~-allylo-xy-3-chloro-phenylacetic acid, 2-(3--benzoylphenyl)-propionic acid, 2-(4-isobu-tylphenyl)-propionic acid, d-2(6-methoxy-2-naphtyl)-propionic acid, 2-(6-rne-thoxy-2-naphtyl)-propionic acid, ~- 3-(trifluorornethyl)-phenylamino -ben-zoic acid and 2- 3-(trifluoromethyl~-phenylamino -nicotinic acid; is that of the relatively low yields and oF the presence of by-products and impurities which are objectionable from the pDint of view of the industrial production and cause expensive and time-consuming purification treatments to be necessarily carried out for the pharmaceutical use.
It has been now found and is another object of the present invention that the problems and disadvantages, as above shortly mentioned, are substantially done away with a process of acidic hydrolysis characterized in that the hydrochlori-de of the ester of isopropylidene pyridoxine with an acid selected in the previously indicated group is refluxed in a hydro-alcoholic medium For the tirne i 4 needed for the reaction to be completed. It has been particularly -found that the hydro-alcoholic medium is advantageously formed a mixture of water and oF a lower aliphatic alcohol9 in a ratio water/alcohol o~ between 1: 2 and 1 0 5by volume, the reaction mixture being maintained under stirring for an extended time of the order of some hours, until the hydrolysis is completed.
The desired raw pr~oduct is thereby obtained and is crystallized frorn a solvent, preferably methylisobutylketone, with high yields and purity.
In the following examples, having illustrative but not limitative purpose, the preparation o-f the compounds of the invention is described:
_XAMPLE 1 Isopropylidene ~yr-tiox_ne ester of 1-(o-chlorobenzoyl)-2-rnethyl-5-methoxy-indol- 3- acetic acid 0-1 ~CL

H Cl a) chloride of ~ l (p_chlorobenzoyl)-2-rnethyl-5-methoxy-indol-3-acetic acid.
A glass flask is charged with 900 mls of benzene, 159 9 of thionyl chloride and 400 9 of 1-(p-chlorobenzoyl)-2-rnethyl-5-methoxy-indol-3-acetic acki, and a fluid stirrable mass is obtained, which is heated in a water bath up to a temperature of 65C. Within about 4 hours the end of the gas development is observed in a gas trap.
The reaction mass is cooled and the crystallized chloride is filtered in a porous filter. It is washed with cold benzene and dried under vacuum.
From the filtration mother liquors, after concentration, further chloride crystallizes.
There are obtained 322 9 of the chloride 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-indol-3-acetic acid with a yield oF 76%.

. . , b) Hydrochlorid~ of the (3,~-isopropylidene)-pyridoxine es~er oF 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-ir~dol-3-acetic acid In a three neck Qlass flask, having stirrer, thermometer and cooler, 320 g of the chloride obtained in the step (a) are charged and are dissolved in 670 mls of anhydrous chloroform. The temperature of the solution is reduced, by means of external brine, to 4C.
A solution of 178 9 of (3,4-isopropylidene)-pyridoxine dissolved in 500 mls of chloroform is separately prepared and added with 96 9 of triethylamine. The tempera~ure of the solution is reduced to 4C and the addition of the chloride solution is slowly started, care being taken that the reaction temperature does not overcome the value of 10C.
Upon the addition is completed, the reaction mixture is rnaintained under stirring for 20 hours, and the temperature slowly increases up to 20C within about 12 hours.
The reaction mixture is then washed with water, with water made acidic with HCI, with water supplemented with sodium carbonate and lastly with water again. The chloroformic extract is separated in a flask, dried over Na2 S04 and concentrated.
A greenish oil is obtained, which is dissolved with methylisobutylketo-ne and slowly crystallized; it is then filtered and converted to the hydrochloride by taking the mass with anhydrous acetone and bubbling gaseous hydrogen chloride.
326 9 of product having melting point of 180-190C (yield: 65% of the theoretical value) are obtained, it being soluble in cold chloroform and in hot ethanol; the product is poorly soluble in hot N,N-dimethylfor-mamide and insoluble in water.
c) (3,4-isopropylidene)-pyridoxine ester of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-indol-3-acetic acid. 50 9 oF the ester hydruchloride as obtained in the step (b) are added to a mixture of 550 mls of methyl-isobutylketone and 250 mls of water.
7 mls of 33U/o NH40H are added. The active compound is completely dissolved and frorn the solution, after concentration to dryness9 an oil is obtained which, by adding 100 mls of ethanol (95C), cloes completely cry3tallize~ There are obtained 36 9 of a product having 95~2 - G -melting point oP 106-107DC, having a unique chromatographic spot.
By operating in the same manner the corresponding esters of the 5-(2.4-difluorophenyl)-salicylic acid are obtained, with the following properties:
1) 5-(2,4-d,ifluoro-phenyl)-salicyloyl ester of (3.4-isopropylidene)-pyri-doxine hydrochloride, having melting point of 172-173C, which by chromatographic analysis is in pure form and in accord~nce with the reference data. ~sorfv~ e B~ 2) 5-(2,4-difluorophenyl)-salicyloyl ester of (3,4-i~e~) pyrido-xine having melting point of 99-102aC., in form of white, microcry-stalline powder. The U.V., I.R. and N.M.R. spectra correspond to the theoretical data.
E,<AMPLE 2 Pyridoxine ester o_1- p-chlorobenzoyl)-2-methyl-5-methoxy-indol-3-acetic 9--This example specifically relates to the hydrolysis step with exclusive removal of the isopropylidene group. In a glass flask, having stirrer and cooler, 120 9 of the hydrochloride obtained in the step (b) of Example 1 are charged together with 1000 mls of methanol of technical grade and 250 mls of water.
The mixturs is refluxed for 10 hours (at about 65C), the hydrolysis pattern being monitored by chrornatography.
The mixture i5 cooled and then poured into about 1500 mls of water-arnmonia solution, whereby the raw hydrolized product precipitates, having melting point o-f 79-80UC.
The product is then crystallized from methylisobutylketone, after passing onto decoloring charcoal, and there are obtained 75 9 of product with a yield o-f 72~/D
of the theor~tical value and with a melting point Df 145-147C.

Pyridoxine ester of 5-(2.4-difluorophenyl)-saly-c)/!-i-c-acid.
In a 1000 ml flask, having a stirrer, a thermometer and a heating bathg 50 g o-f5-(2.4-difluorophenyls)-salicyloyl ester of (3.4-isopropylidene)-pyridoxine hy-drochloride are charged and added with 500 mls of methanol and 125 mls o-f water.
The reaction mixture is refluxed, the reaction being monitored by taking I
S samples for the chromatographic assay.

After 6 hour reaction, the resul-ting mixture, in form of heterogeneous solution, is poured into 2000 mls of water under stirring, ammonia being then added. There are obtained 32 g of raw product which are crystallized from methylisobu-tylke-tone and filtered, thus forming 13.7 g of 1 a pure produc-t, which is in accordance wi-th the standard i data of the chromatographic analysis, having melting point 167-170C.

j The compounds of the invention have been subjected S to pharmacological and toxicological investigation, which revealed tha-t, in comparison with the free acids, there are ~chieved those highly desirable results of lower toxicity and greater gas-tric tolerability, the therapeutical ac-tivity remaining unchanged. In the following resuming -table the ~ results obtained for -the esters of the Indomethacin are J reported. In the determination of the acute -toxicity, car-i 20 ried ou-t in the rat, -the me-thod of Litchfield and Wilcoxon (J. Pharmacol. Exp. Therm., 96,99, 1949) has been adopted.

As regards -the analgesic ac-tivity, the evaluation has been carried ou-t according to the method of Randall and Selitto (Arch.Ing.pharmacodyn.~ 4o9~l949).

As regards the anti-inflammatory ac-tivity, -the ED50 in the normal rat has been evaluated according to Winter et al. (Proc.Soc.Exp.Biol.Med.,111,544,1962).
Lastly, with respect to the ulterogenic acitivity, indicated as UD50, it has been determined by adminis-tering , per os the compounds to fasted rats and evaluating the pre-3 sence of gastric lesions at predetermined -times af-ter the ¦ 35 administrationO

The UD50 has been also calculated according to -the aforesaid method of Li-tchfield and Wilcoxon~

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o-The present invention is further directed to pharmaceutical compositionscontaining, as the active principle, a compound of formula (1) in combination with a pharmaceutical excipient or vehicle, and -formulated for the oral, parenteral, rectal or topical administration.
The compositions ~or the oral administration can be in solid form (capsules, tablets, pills, together with excipients such as lactose, starch, talc, magnesiurn stearate) or in liquid form (syrups, drops, suspensions, with suitable liquid vehicles comprising water and sweetening, ~lavoring, dispersing and/or other agents).
The compositions for the parenteral administration consist of injectable solutions, either aqueous (comprisEng also mixtures of water and glycols) and oily.
For the oral and parenteral admnistration forms, the compounds of the invention are prefersbly used as an addition salt with a non toxic and pharmaceutically acceptable acid, such as for instance hydrochlorides9 hydrobromides, sulfates, acetates, succinates, fumarates, tartrates, salicyla-tes, nicotinates etc.
For the rectal and topical preparations there are lastly used standard bases forsuppositories and, respectively, for creams and ointments.
The pharmaceutical compositions of the present invention are p~eferably formulated so as to permit a untary dose of the active principle to be administered, consistently with the efficacy of the active compound and with the desired effect.
The unitary doses of the active principle for the oral and parenteral administration can be suitably comprised between 100 and lûO0 mg, preferably between 250 and 700 mg, whereas those for rectal administration can be comprised between 200 and 1500 mg, preferably between 50û and 1000 mg lastly, for the topical application, the concentration of the active principle by weight is of between 1 and 10%, and preferably is 5%.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of derivatives of pyridoxine having the general formula -IMAGE-(I) wherein the R radicals represent a hydrogen atom, or con-jointly, an isopropylidene group, and R1 represents the resi-due of an acid selected in -the group comprising l-(p-chloro-benzoyl)-2-methyl-5-methoxy-indol-3-acetic acid and 5-(2,4-difluorophenyl)-salicylic acid, or an addition salt thereof, with a non-toxic and pharmaceutically acceptable, inorganic or organic acid, wherein isopropylidene pyridoxine is reacted with the halide of the acid, in the presence of an acid acceptor as the catalyst when required, the resulting ester is hydrolized by refluxing the ester of isopropylidene pyridoxine in a hydro-alcoholic medium, until the reaction is completed, and when the free base is obtained and the salt is required salifying the free base and when the salt is obtained and the free base required converts the salt to the free base.

2. A process according to claim 1, in which said hydro-alcoholic medium comprises a mixture of water and of a loweraliphatic alcohol in a volume ratio of between 1:2 and 1:5.

3. A process according to claim 2, in which said lower aliphatic alcohol is methanol and the ratio between water and alcohol is 1:4.

4. A process according to claim 1, 2 or 3, in which the catalyst is a tertiary amine.

5. A process according to claim 1, 2 or 3, in which the hydrochloride of the ester is refluxed.

6. A derivative of pyridoxine and isopropylidene pyridoxine having the formula:

-IMAGE-(I) wherein the R radicals represent a hydrogen atom or, con-jointly, an isopropylidene group, and R1 represents the resi-due of an acid selected in the group comprising 1-(p-chloro-benzoyl)-2-methyl-5-methoxy-indol-3-acetic acid and 5-(2,4-difluorophenyl)-salicyclic acid, or an addition salt there-of, with a non-toxic and pharamaceutically acceptable, in-organic or organic acid, whenever prepared or produced by the process as claimed in claim 1, 2 or 3, or an obvious chemical equivalent thereof.

7. A process according to claim 1, in which the product is obtained in the form of a hydrochloride, hydro-brornide, sulfate, acetate, succinate, maleate, fumarate, tartarate, salicylate, cyclohexylsulfamate, or nicotinate.

8. A derivative of formula I given in claim 1, wherein R and R1 are as in claim 1, in form of a hydrochloride, hydrobromide, sulfate, acetate, succinate, maleate, fumarate, tartarate, salicylate, cyclohexylsulfamate or nicotinate, whenever prepared or produced by the process claimed in claim 7 or an obvious chemical equivalent thereof.

9. A process according to claim 1, which comprises slowly adding (3,4-isopropylidene)-pyridoxine in chloroform and in the presence of triethylamine at a temperature not exceeding 10°C to a solvent of the chloride of l-(p-chloro-benzoyl)-2-methyl-5-methoxy-indol-3-acetic acid in anhydrous chloroform; washing the product obtained and treating the product obtained in anhydrous acetane with gaseous hydrogen chloride.

10. The hydrochloride of the (3,4-isopropylidene)-pyridoxine ester of l-(p-chlorobenzoyl)-2-methyl-5-methoxy-indol-3-acetic acid, whenever prepared or produced by the process as claimed in claim 9 or an obvious chemical equi-valent thereof.

11. A process according to claim 9, in which the hydrochloride obtained is treated in aqueous methylisobutyl-ketone with ammonium hydroxide.

12. (3,4-isopropylidene)-pyridoxine ester of l-(p-chlorobenzoyl)-2-methyl-5-methoxy-indol-3-acetic acid, when-ever prepared or produced by the process as claimed in claim 11 or an obvious chemical equivalent thereof.

13. A process according to claim 1, which comprises slowly adding (3,4-isopropylidene)-pyridoxine in chloroform and in the presence of triethylamine at a temperature not exceeding 10°C to a solvent of (2,4-difluorophenyl)-salicy-lic acid in anhydrous chloroform; washing the product ob-tained and treating the product obtained in anhydrous ace-tane with gaseous hydrogen chloride.

14. 5-(2,4-difluorophenyl)-salicylic ester of (3,4-isopropylidene)-pyridoxine hydrochloride, whenever prepared or produced by the process as claimed in claim 13 or an obvious chemical equivalent thereof.

15. A process according to claim 13, in which the hydrochloride obtained is treated in aqueous methyl isobutyl ketone with ammonium hydroxide.

16. 5-(2,4-difluorophenyl)-salicyloyl ester of (3,4-isopropylidene)-pyridoxine, whenever prepared or pro-duced by the process as claimed in claim 15 or an obvious chemical equivalent thereof.

17. A process according to claim 9, in which the hydrochloride of the (3,4-isopropylidene)-pyridoxine ester of 1-(p-chlorobenzoyl)-2-me-thyl-5-me-thoxy-indol-3-ace-tic acid obtained is refluxed in a methanol-water mixture.

18. Pyridoxine ester of l-(p-chlorobenzoyl)-2-methyl-5-methoxy-indol-3-acetic acid, whenever prepared or produced by the process as claimed in claim 17 or an obvious chemical equivalent thereof.

19. A process according to claim 13, in which the 5-(2,4-difluorophenyl)-salicyloyl ester of (3,4-isopropyli-dene)-pyridoxine hydrochloride obtained is refluxed in a methanol-water mixture.

20. Pyridoxine ester of 5-(2,4-difluorophenyl)-salicylic acid, whenever prepared or produced by the process as claimed in claim 19 or an obvious chemical equivalent thereof.